U.S. patent number 5,266,718 [Application Number 07/898,916] was granted by the patent office on 1993-11-30 for ethanolamine benzoate compounds.
This patent grant is currently assigned to Adir et Compagnie. Invention is credited to Michelle Boulanger, Jacques Duhault, Pierre Hugon, Francoise Lacour, Michel Wierzbicki.
United States Patent |
5,266,718 |
Wierzbicki , et al. |
November 30, 1993 |
**Please see images for:
( Certificate of Correction ) ** |
Ethanolamine benzoate compounds
Abstract
New ethanolamine benzoate compounds which can be used as
medicaments and correspond to the formula: ##STR1## wherein R is as
defined in the description, in the form of racemic compounds and
enantiomers. These new compounds and their physiologically
tolerable salts can be used therapeutically for treatment of
insulin-resistance states.
Inventors: |
Wierzbicki; Michel (L'Etang la
Ville, FR), Hugon; Pierre (Rueil Malmaison,
FR), Duhault; Jacques (Croissy sur Seine,
FR), Lacour; Francoise (Vincennes, FR),
Boulanger; Michelle (Marly le Roi, FR) |
Assignee: |
Adir et Compagnie (Courbevoie,
FR)
|
Family
ID: |
27252465 |
Appl.
No.: |
07/898,916 |
Filed: |
June 12, 1992 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
883207 |
May 14, 1992 |
|
|
|
|
Foreign Application Priority Data
|
|
|
|
|
Jun 14, 1991 [FR] |
|
|
91 07289 |
|
Current U.S.
Class: |
560/36; 560/106;
560/37 |
Current CPC
Class: |
C07C
219/14 (20130101); C07C 235/34 (20130101); C07C
233/51 (20130101); C07C 2603/18 (20170501) |
Current International
Class: |
C07C
219/14 (20060101); C07C 219/00 (20060101); C07C
233/51 (20060101); C07C 235/34 (20060101); C07C
233/00 (20060101); C07C 235/00 (20060101); C07C
101/34 () |
Field of
Search: |
;560/106,36,37
;514/513,530,540 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Dees; Jose G.
Assistant Examiner: Barts; Samuel
Attorney, Agent or Firm: Hueschen; Gordon W.
Parent Case Text
The present application is a continuation-in-part of our
prior-filed co-pending application Ser. No. 07/883,207 filed May
14, 1992, now abandoned.
Claims
We claim:
1. An ethanolamine benzoate compound selected from those of formula
I: ##STR48## in which: R represents:
hydrogen, or
a group of formula: ##STR49## in which R' represents: a) a radical
of formula: ##STR50## in which: R" represents hydrogen or
straight-chain or branched alkyl containing 1 to 5 carbon atoms
inclusive,
R.sub.1 and R.sub.2, which are the same or different, each
represents hydrogen or straight-chain or branched alkyl or alkoxy
each having 1 to 5 carbon atoms inclusive, and m and n are the same
or different and each represents 1, 2 or 3;
b) a fluorenyl radical of formula: ##STR51## in the racemic form or
in the form of an enantiomer thereof, and physiologically-tolerable
acid addition salts thereof.
2. A compound of claim 1 which is:
1-2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(.alpha.-fluoren-9-ylacetylamino)ethyl]benzoate
hydrochloride.
3. A compound of claim 1 which is:
d-2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(.alpha.-fluoren-9-ylacetylamino)ethyl]benzoate
hydrochloride.
4. A compound of claim 1 which is:
d1-2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(.alpha.-fluoren-9-ylacetylamino)ethyl]-benzoate
hydrochloride.
5. A compound of claim 1 which is:
1-2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(benzhydrylacetylamino)ethyl]benzoate hydrochloride.
6. A compound of claim 1 which is:
d1-2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
benzoate hydrochloride.
7. A compound of claim 1 which is:
1-2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
benzoate hydrochloride.
8. A compound of claim 1 which is:
d-2-[(b-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
benzoate hydrochloride.
9. A pharmaceutical composition useful for regulating glucide and
lipid metabolism comprising as active ingredient an amount of a
compound according to claim 1 effective for said purpose together
with a pharmaceutically-acceptable excipient.
10. A method for treating a mammal afflicted with an
insulin-resistance state, comprising the step of administering to
the said mammal an amount of an ethanolamine benzoate compound
selected from those of formula I: ##STR52## in which: R
represents:
hydrogen, or
a group of formula: ##STR53## in which R' represents: a fluorenyl
radical of formula: ##STR54## in the racemic form or in the form of
an enantiomer thereof, and physiologically-tolerable acid addition
salts thereof, which is effective for alleviation of the said
condition.
Description
The present invention relates to new ethanolamine benzoate
compounds, a process for their preparation and pharmaceutical
compositions containing them.
It relates especially to ethanolamine benzoate compounds of formula
I: ##STR2## wherein: R represents:
a hydrogen atom, or
a group of formula: ##STR3## wherein R' represents: a) either a
radical of formula: ##STR4## wherein: R" represents a hydrogen atom
or a straight-chain or branched alkyl radical containing from 1 to
5 carbon atoms,
R.sub.1 and R.sub.2, which are the same or different, each
represents a hydrogen atom or a straight-chain or branched alkyl or
alkoxy radical each having from 1 to 5 carbon atoms, and m and n
are the same or different and each represents 1, 2 or 3;
b) or a fluorenyl radical of formula: ##STR5## in the form of a
racemic compound or in the form of enantiomers.
The prior art is illustrated especially:
by French Patents 1 517 587 and 6564 M which respectively relate
to:
compounds of formula: ##STR6## wherein: n represents, inter alia,
the value 2, and
R'.sub.0 represents a hydrogen atom or a group COR".sub.0, R".sub.0
being, inter alia, an optionally substituted phenyl radical,
and
the use of these compounds as medicaments in the treatment in
particular of obesity, pain and epilepsy; and
by U.S. Pat. No. 4,237,165, which relates to pharmaceutical
compositions comprising either
1-(3-trifluoromethylphenyl)-2-(.beta.-hydroxyethyl)aminopropane or
1-(3-trifluoromethylphenyl)-2-(.beta.-benzoyloxyethyl)aminopropane,
which can be used in the treatment of disorders of the
metabolism.
Substantial structural modifications have resulted in the compounds
of formula I of the present invention, which regulate the
metabolism of glucides and lipids and counter the oxidation of LDLs
but have no effect on the level of cerebral serotonin, which is not
true of the compounds of the prior art mentioned above which are
inactive with respect to the oxidation of LDLs and do modify the
level of cerebral serotonin, as demonstrated by the pharmacological
study described in Example 10.
The present invention also relates to a process for the preparation
of compounds of formula I which is characterised in that:
the acid of formula II: ##STR7## wherein R has the meaning given
hereinbefore, is converted into a salt of formula II': ##STR8##
wherein R has the meaning given hereinbefore and M is an alkali
metal or alkaline earth metal;
the latter is reacted with a halogenated compound formula III:
##STR9## wherein: Z represents a hydrogen atom or a methyl radical,
and
Hal represents a halogen atom, such as a chlorine, bromine or
iodine atom;
and the compound so obtained of formula IV: ##STR10## wherein R and
Z have the meanings given hereinbefore, is catalytically
debenzylated.
The compounds of formula III wherein Z represents a hydrogen atom
result in racemic compounds IV.
The compounds of formula III wherein Z represents a methyl radical
result either in racemic compounds IV or in laevorotatory or
dextrorotatory enantiomers depending on whether the
.alpha.-methylbenzyl group bonded to the nitrogen atom is RS, S or
R, respectively.
Certain starting compounds of formula II: ##STR11## are known.
This is true of acids of formula II wherein R represents:
a hydrogen atom (in which case the compound II is benzoic acid, a
commercial product)
or a group: ##STR12## cf: European Journal of Pharmacology (1987),
141-2, 243-251; or the fluoren-9-ylacetylaminoethyl radical, cf.:
U.S. Pat. No. 4,136,197.
In the other cases, that is to say when R represents a: ##STR13##
group wherein R.sub.1, R.sub.2, R", n and m are as defined
hereinbefore but, in addition, R.sub.1, R.sub.2 and R" do not
simultaneously represent a hydrogen atom, the corresponding
compounds II are new products which, as such, form part of the
present invention.
There are thus included within the present invention, as new
starting materials that can be used for the synthesis of compounds
of formula I - which can themselves be used as medicaments -
compounds II corresponding more specifically to formula IIa:
##STR14## wherein R.sub.a represents a group of formula A:
##STR15## wherein: m and n have the meanings given
hereinbefore,
R".sub.a represents a hydrogen atom or a straight-chain or branched
alkyl radical containing from 1 to 5 carbon atoms, and
R.sub.1a and R.sub.2a, which are the same or different, each
represents a hydrogen atom or a straight-chain or branched alkyl or
alkoxy radical each having from 1 to 5 carbon atoms, with the
proviso, however, that R.sub.1a, R.sub.2a and R".sub.a do not
simultaneously represent a hydrogen atom.
The compounds II that are novel were prepared by converting acids
of formula V: ##STR16## wherein R".sub.a, R.sub.1a, R.sub.2a, m and
n have the meanings given hereinbefore, into an acid chloride or
mixed anhydride of formula V.sub.a or V.sub.b respectively:
##STR17## which are condensed
a) either with an amino acid of formula VIa: ##STR18## to obtain a
compound of formula IIa directly, a formula which can be more
precisely drawn as follows: ##STR19## wherein R".sub.a, R.sub.1a,
R.sub.2a, m and n have the meanings given hereinbefore,
b) or with an amino ester of formula VIb: ##STR20## wherein W is a
straight-chain or branched alkyl radical having from 1 to 5 carbon
atoms, to yield a compound of the general formula II'a: ##STR21##
wherein R".sub.a, R.sub.1a, R.sub.2a, m, n and W have the meanings
given hereinbefore,
which is hydrolysed to form an acid of formula IIa.
In the case where R".sub.a represents a hydrogen atom, the
corresponding acids V were themselves obtained by HORNER reaction
between the ketone of formula B: ##STR22## and ethyl
phosphonoacetate [(C.sub.2 H.sub.5 O).sub.2 OP--CH.sub.2
--COOC.sub.2 H.sub.5 ], followed by catalytic hydrogenation of the
resulting compound of formula C: ##STR23## to yield the ester of
formula D: ##STR24## which is then hydrolysed to form the
corresponding acid of formula E: ##STR25## (R.sub.1a, R.sub.2a m
and n in each of the formulae having the meanings given
hereinbefore), that is to say to form the acid V wherein R"
represents a hydrogen atom.
In the case where R".sub.a represents a straight-chain or branched
alkyl radical containing from 1 to 5 carbon atoms, the
corresponding acids V were themselves obtained by COPE condensation
between the ketone of formula B': ##STR26## (wherein R.sub.1a and m
are as defined hereinbefore and Alk represents a straight-chain or
branched alkyl radical containing from 1 to 5 carbon atoms)
and ethyl cyanoacetate (NC--CH.sub.2 --COOC.sub.2 H.sub.5) in
toluene, in the presence of acetic acid and ammonium acetate, to
yield the ethylene compound of formula F: ##STR27## which is then
subjected to the action of an organomagnesium compound of formula
G: ##STR28## (R.sub.2a and n being as defined hereinbefore and X
representing a halogen atom)
to yield the compound of formula H: ##STR29## (wherein R.sub.1a,
R.sub.2a, m, n and Alk are as defined hereinbefore), which compound
H is hydrolysed to form the acid of formula J: ##STR30## which is
decarboxylated to yield the nitrile of formula K: ##STR31## which
is in turn hydrolysed to form the desired acid of formula L:
##STR32## (wherein R.sub.1a, R.sub.2a, m, n and Alk are as defined
hereinbefore); that is to say to form an acid of formula V wherein
R".sub.a represents a straight-chain or branched alkyl radical
containing from 1 to 5 carbon atoms.
The starting materials of the general formula III: ##STR33##
wherein Hal and Z are as defined hereinbefore, were obtained in
accordance with the following reaction procedure: J ##STR34## and
the latter is recrystallised in hydrochloride form. When Z
represents a methyl radical, depending on whether the starting
.alpha.-methylbenzylamine is R or S, the hydrochloride of compound
(f) is obtained by recrystallisation in the form of one or the
other diastereoisomer.
The benzylated amine of formula f (optionally in pure
diastereoisomer form) is then alkylated by means of ethyl
bromoacetate in the presence of a base, such as potassium
carbonate, to yield the compound of formula g: ##STR35## which is
then reduced with LiAlH.sub.4 to form the alcohol of formula h:
##STR36## The latter is then converted into the halide III by means
of a halogenated compound (such as, for example, SOCl.sub.2,
PCl.sub.5 or POCl.sub.3 to obtain, more precisely, a compound of
formula III wherein Hal represents a chlorine atom, that is:
##STR37##
The present invention also relates to a process for the preparation
of compounds of the general formula I which is characterised in
that:
a primary acid (optionally chiral) of formula VII: ##STR38## is
reacted with ethylene oxide to obtain the compound of formula VIII:
##STR39## which is converted into the chloride of formula IX:
##STR40## and the latter is coupled with a salt of formula II':
##STR41## wherein R and M are as defined hereinbefore, to yield a
compound of formula I: ##STR42##
The compounds of formula I can be converted into addition salts
with acids, which salts, as such, form part of the present
invention.
There may be mentioned as acids for the formation of those salts,
for example, in the mineral series, hydrochloric, hydrobromic,
nitric, sulphuric and phosphoric acid and, in the organic series,
acetic, propionic, maleic, fumaric, tartaric, oxalic, benzoic,
methanesulphonic and isethionic acid.
The compounds of formula I and their physiologically tolerable
addition salts have valuable pharmacological and therapeutic
properties, especially properties regulating the metabolism of
glucides and lipids. Moreover, they cause a moderate reduction in
arterial pressure.
More precisely, the compounds of the present invention improve the
efficacy of insulin at a peripheral and/or hepatic level, resulting
in an improvement in glucose tolerance and in moderate
hyperglycemia, where it exists, without the risk of hypoglycemia,
as well as in a reduction in hyperinsulinemia. Furthermore, the
compounds of the present invention reverse insulin resistance
induced by high levels of amylin.
They also reduce hypertriglyceridemia and combat LDL (low density
lipoprotein) oxidation, which has an implication in the prevention
of macroangiopathies.
They cause a modest reduction in weight associated with a reduction
in food intake, not associated with a serotoninergic mechanism, and
as a result of the latter two properties they are differentiated
from existing products in that field (benfluorex,
fenfluramine).
Those properties enable them to be used therapeutically especially
for the treatment of non-insulin-dependent diabetics not treated by
diet, non-insulin-dependent diabetics treated with blood
sugar-reducing medicaments, diabetics that are insulin-dependent or
not treated with insulin, or non-hyperglycemic, hypertensive or
non-hypertensive, patients having hyperinsulinemia (i.e. android
obesity) and all exhibiting a resistance to insulin, induced or not
by amylin.
The products of the invention are thus used in the treatment of
diabetes, obesity, syndrome X (by way of improvement in the effect
of insulin at the periphery and/or with respect to the liver,
decrease in triglycerides and in LDL oxidation, associated with a
moderate reduction in weight), and in the treatment of hypertension
in patients who are resistant to insulin or have associated or
unassociated metabolic anomalies such as, for example,
hyperinsulinemia, dyslipemia and hyperglycemia, these having been
induced or not by amylin.
The present invention also relates to pharmaceutical compositions
comprising as active ingredient a compound of formula I or a
physiologically tolerable salt thereof, mixed with or in
association with one or more appropriate pharmaceutical
excipients.
The so-obtained pharmaceutical compositions are generally presented
in dosage form comprising from 25 to 100 mg of active ingredient.
They may be in the form of tablets, dragees, capsules,
suppositories or injectable or drinkable solutions, and may be
administered by the oral, rectal or parenteral route.
The dosage may vary, especially in accordance with the age and
weight of the patient, the route of administration, the nature of
the disorder and associated treatments, and ranges from 25 to 100
mg of active ingredient per administration from 1 to 4 times per
day.
The following Examples illustrate the invention.
EXAMPLE 1
Levorotatory isomer of
2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(.alpha.-fluoren-9-ylacetylamino)ethyl]benzoate
hydrochloride ##STR43##
8.3 g of
1-N-(.beta.-chloroethyl)-N-(.alpha.-phenylethyl)-N-[(.beta.-methoxy-.beta.
-meta-trifluoromethylphenyl)ethyl]amine hydrochloride are stirred
in 100 ml of water, 100 ml of ether and 2.5 ml of concentrated
sodium hydroxide solution. The ethereal phase is collected by
decanting, and dried over MgSO.sub.4 ; the solvent is distilled off
and the residue is dissolved in 50 ml of anhydrous
dimethylformamide.
That solution is then slowly poured into a flask containing 7.3 g
of para-[2-(fluoren-9-ylacetylamino)-ethyl]benzoic acid, 2.7 g of
K.sub.2 CO.sub.3 and 100 ml of dimethylformamide, which together
have beforehand been heated at 60.degree. C. for 45 minutes.
After the addition of the chlorinated compound, the reaction
mixture is heated to 90.degree. C. for 3 hours under nitrogen. The
solvent is distilled off in vacuo and the residue is taken up in
ether. The potassium chloride precipitate is filtered off and the
ether is distilled off. The residue obtained (approximately 13 g)
is filtered through 300 g of silica using a mixture of
dichloromethane/ethyl acetate (95/5) as eluant.
In this manner 8 g of compound IV of formula: ##STR44## are
obtained. 7 g of that compound dissolved in 160 ml of anhydrous
isopropanol are hydrogenated under a hydrogen pressure of
approximately 90 lbs, at a temperature of 50.degree. C., until
complete absorption of the necessary amount of hydrogen.
The solution is then filtered through talc, the solvent is
distilled off and the residue is filtered through 100 mg of silica
using a CH.sub.2 Cl.sub.2 /CH.sub.3 COOC.sub.2 H.sub.5 mixture
(50/50) as eluant.
The solvent is distilled off from the fraction containing the
product. The residual oil is taken up in ether and a slight excess
of ethereal hydrogen chloride solution is added. The resulting
precipitate is filtered and washed with ether, yielding 4.5 g of
the levorotatory isomer of
2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(.alpha.-fluoren-9-ylacetylamino)ethyl]benzoate
hydrochloride.
Rotatory power: (c=1% in ethanol).
[.alpha.]589: -29.7
[.alpha.]578: -30.6
[.alpha.546: -34.7
[.alpha.]436: -58.3
[.alpha.]365: -90.9.
The para-[2-(fluoren-9-ylacetylamino)ethyl]benzoic acid starting
material was prepared in accordance with U.S. Pat. No. 4,136
197.
The
1-N-(.beta.-chloroethyl)-N-(.alpha.-phenylethyl)-N-[(.beta.-methoxy-.beta.
-meta-trifluoromethylphenyl)ethyl]amine hydrochloride starting
material was prepared as follows:
a) 225 g of 3-trifluoromethylbromobenzene are added dropwise to a
mixture of 27 g of magnesium and 500 ml of anhydrous ether to which
an iodine crystal has previously been added. The reaction is
affected in such a manner as to ensure a slight reflux of the
ether. Once the magnesium has dissolved, 232 g of
1-methoxy-1,2-dibromoethane (prepared in accordance with the
technique described in Organic Syntheses vol. IV, p 748, replacing
the ethanol with methanol) are slowly added.
Refluxing is maintained for 1 hour once addition is complete. The
mixture is then cooled and subsequently hydrolysed with 250 ml of
water. After decanting, the ethereal phase is washed with water and
then dried.
The solvent, and then the product, are distilled off under reduced
pressure. 203 g of
3-trifluoromethyl-1-(2-bromo-1-methoxyethyl)benzene are obtained
(b.p..sub.13 Pa =68.degree. C.).
b) 202 g of that brominated compound and 173 g of
(S)-.alpha.-methylbenzylamine are refluxed in 714 ml of xylene for
6 hours.
The xylene is then distilled off and the residue is taken up in
ether. The .alpha.-methylbenzylammonium bromide is removed from the
resulting filtrate, which is then distilled to yield 144 g of
product which boils at 125.degree.-128.degree. C. under 13 Pa.
94 ml of 5N ethereal hydrogen chloride are added to that compound
dissolved in ether. The resulting precipitate is filtered, washed
with ether and recrystallised twice from 550 ml of isopropanol each
time, yielding 80 g of the pure diastereoisomer.
c) 21 g of the latter are reacted with 12 g of ethyl bromoacetate
and 9.8 g of potassium carbonate in 65 ml of anhydrous ethanol. The
reaction mixture is refluxed for 8 hours, 2 ml of ethyl
bromoacetate and 2.5 g of potassium carbonate are then added, and
the mixture is heated again for 4 hours. The mineral compound is
filtered off, the ethanol and the excess bromoacetate are distilled
off, and the oil which remains is used as such.
d) 27 g of the ester so obtained are reacted with 3.78 g of
LiAlH.sub.4 in 150 ml of anhydrous tetrahydrofuran under reflux for
5 hours.
The mixture is then hydrolysed with 3.8 ml of water, then with 3.8
ml of 4N NaOH and finally with 11.4 ml of water.
The organic phase is filtered and concentrated and used as
such.
e) 22.9 g of the alcohol so obtained are dissolved in 65 ml of
chloroform. 10.5 ml of 6N ethereal hydrogen chloride are added
dropwise to the solution. The solvent is evaporated off, the
residue is taken up in 65 ml of chloroform, and 8.2 g of thionyl
chloride are added dropwise thereto.
The whole is refluxed for 5 hours and then the solvent is distilled
off. The residue is taken up in 150 ml of ethyl acetate and
dissolved with the application of heat. The mixture is allowed to
cool until a slight precipitate is formed corresponding to:
##STR45## which is removed accordingly.
The solvent is then distilled off from the remaining solution and
the product remaining (which is the
1-N-(.beta.-chloroethyl)-N(.alpha.-phenylethyl)-N-[(.beta.-methoxy-.beta.-
meta-trifluoromethylphenyl)ethyl]amine hydrochloride) is used as
such.
EXAMPLES 2 TO 7
The following compounds were prepared by proceeding as described in
Example 1:
2. Dextrorotatory isomer of
2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(.alpha.-fluoren-9-ylacetylamino)ethyl]benzoate
hydrochloride, rotatory power (c=1% in ethanol):
[.alpha.]589: +30.0
[.alpha.]578: +31.3
[.alpha.]546: +35.8
[.alpha.]436: +61.4
[.alpha.]365: +95.0.
3.
dl-2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(.alpha.-fluoren-9-ylacetylamino)ethyl]benzoate
hydrochloride.
4. Levorotatory isomer of
2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(benzhydrylacetylamino)ethyl]benzoate hydrochloride.
Rotatory power (c=1% in ethanol at 21.degree. C.):
[.alpha.]589: -32.3
[.alpha.]578: -33.5
[.alpha.]546: -38.1
[.alpha.]436: -64.5
[.alpha.]365: -100.7
5.
dl-2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
benzoate hydrochloride, m.p. (Kofler): 122.degree.-123.degree.
C.
6. Levorotatory isomer of
2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
benzoate hydrochloride.
Rotatory power (c=1% in ethanol at 23.degree. C.):
[.alpha.]589: -52.9
[.alpha.]578: -55.1
[.alpha.]546: -62.7
[.alpha.]436: -106.6
[.alpha.]365: -167.3.
7. Dextrorotatory isomer of
2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
benzoate hydrochloride.
Rotatory power (c=1% in ethanol at 23.degree. C.):
[.alpha.]589: +51.5
[.alpha.]578: +53.9
[.alpha.]546: +61.1
[.alpha.]436: +103.6
[.alpha.]365: +152.2
EXAMPLES 8 and 9
The new starting materials of the formula IIa were prepared in
accordance with the method illustrated in the following
Examples:
8.
Para-{2-[N-(bis-4,4'-n-pentyloxybenzhydrylacetyl)amino]ethyl}benzoic
acid ##STR46##
a) Para-n-pentyloxybromobenzene: 276 g of anhydrous potassium
carbonate are added to 173 g of p-bromophenol dissolved in 1800 ml
of methanol. After stirring, the reaction mixture is treated with
164 ml of n-bromopentane and maintained at reflux for 4 hours with
stirring.
After cooling, 3 liters of water are added and the methanol is
removed under water-jet vacuum.
After extraction with 2 liters of ether and then twice with 1 liter
of ether each time, the organic solutions are combined and washed 3
times with 1 liter of water each time. After drying over anhydrous
MgSO.sub.4, the solvent is evaporated off in vacuo and the residue
is distilled.
222.8 g of para-n-pentyloxybromobenzene (b.p./.sub.13 Pa
=87.degree.-91.degree. C.) are obtained. Yield: 91.6%. b)
Para-n-pentyloxybenzaldehyde: by operating as above starting with
33 g of para-hydroxybenzaldehyde, 74.5 g of potassium carbonate and
45 g of n-bromopentane, 21 g of para-n-pentyloxybenzaldehyde
(b.p./.sub.1.3 Pa =112.degree.-114.degree. C.) were isolated.
Yield: 37%.
c) Ethyl n-pentyloxybenzylidenemalonate: 32.6 g of dimethylamine
hydrochloride and 1.7 g of potassium fluoride are added to 38.5 g
of para-n-pentyloxybenzaldehyde and 31 ml of ethyl malonate
dissolved in 400 ml of anhydrous dimethylformamide. The reaction
mixture is heated with stirring for 18 hours. After the mixture has
been cooled, the solvent is evaporated off in vacuo
(13.times.10.sup.2 to 20.times.10.sup.2 Pa). The residue is taken
up twice in 250 ml of methylene chloride. The organic layer is
washed with 200 ml of a normal hydrochloric acid solution and then
twice with 200 ml of water.
After drying over anhydrous magnesium sulphate, the solvent is
evaporated off under water-jet vacuum. Distillation of the residue
yields 49.8 g of ethyl para-n-pentyloxybenzylidenemalonate
(b.p./.sub.13 Pa =170.degree.-175.degree. C.). Yield: 74.5%.
d) Ethyl
.alpha.-ethoxycarbonyl-.beta.,.beta.-[bis(para-n-pentyloxyphenyl)]propanoa
te:
To a solution of para-n-pentyloxyphenylmagnesium bromide prepared
from 5.8 g of para-n-pentyloxybromobenzene and 0.64 g of magnesium
turnings in 30 ml of tetrahydrofuran (THF) (poured in over a period
of 1 hour under reflux, then maintained at reflux for a further 1
hour) there are added, over a period of 30 minutes, 8 g of ethyl
para-n-pentyloxybenzylidenemalonate dissolved in 25 ml of THF.
After refluxing for 2 hours 30 minutes with stirring, 25 ml of a
normal HCl solution are poured in. The reaction mixture is
extracted three times with 50 ml of water each time and then dried
over MgSO.sub.4. After evaporation the residue is purified by
chromatography. 8.7 g of the desired product are obtained.
e) .beta.,.beta.-[Bis(para-n-pentyloxyphenyl)]propionic acid: 8.5 g
of the product obtained in d) dissolved in 22.5 ml of ethanol are
added to a solution of 6.2 g of potassium hydroxide in 100 ml of
water. The solution obtained is maintained at reflux for 1 hour 30
minutes. After removal of the solvent under water-jet vacuum, the
residue is taken up in 200 ml of water and then acidified with 11
ml of a 37% concentrated HCl solution. The resulting oil is
extracted 3 times with 100 ml of ether each time. After washing
twice with 50 ml of water each time, the ether is dried over
magnesium sulphate and then evaporated in vacuo. 5.6 g of product,
m.p.: 134.degree.-136.degree. C., are obtained, yield: 75%.
The residue is heated for 15 minutes at 180.degree.-190.degree. C.
After washing with petroleum ether, 3.3 g of
.beta.,.beta.-[bis-(para-pentyloxyphenyl)]propionic acid is
obtained, m.p.: 72.degree. C., yield: 67%.
f) Ethyl
para-{2-[N-(bis-4,4'-n-pentyloxybenzhydrylacetyl)amino]ethyl}benzoate:
1.07 ml of triethylamine in 10 ml of THF are added to 3.06 g of the
acid prepared in e) dissolved in 30 ml of THF. After stirring for 1
hour, the resulting solution is added to 0.76 ml of ethyl
chloroformate in 30 ml of THF cooled to 0.degree. C. 1.56 g of
ethyl para-[.beta.-(amino)ethyl]benzoate dissolved in 10 ml of THF
are then poured in over a period of 15 minutes. The temperature
rises to 10.degree. C. After 45 minutes' stirring at room
temperature and 12 hours under reflux, the precipitate is
suction-filtered off and the filtrate is evaporated to dryness in
vacuo. Chromatography yields 3.06 g of the desired benzoate.
g)
Para-{2-[N-(bis-4,4'-n-pentyloxybenzhydrylacetyl)amino]ethyl}benzoic
acid:
3 g of the ester obtained in f), 15 ml of ethanol and 5.7 ml of
normal sodium hydroxide solution maintained at reflux for 2 hours
result in the corresponding benzoic acid.
9. Para-{2-[N-(3-methyl-3,3-diphenylpropionyl)amino]ethyl}benzoic
acid: ##STR47##
a) Ethyl (.alpha.-methylbenzylidene)-cyanoacetate:
60 g of acetophenone, 56.6 g of ethyl cyanoacetate, 7.7 g of
ammonium acetate, 24 g of acetic acid and 100 ml of benzene are
refluxed with stirring and the water formed during the course of
the reaction is removed as the reaction proceeds using a Dean Stark
apparatus.
After 13 hours 40 minutes of heating, 100 ml of ether are added and
the reaction mixture is washed 3 times with 100 ml of water each
time. The organic layer is dried over magnesium sulphate and
concentrated under water-jet vacuum and the residue is distilled,
yielding 58.4 g of ethyl (.alpha.-methylbenzylidene)-cyanoacetate
(b.p./.sub.13 Pa =125.degree.-128.degree. C.).
b) .alpha.-Ethoxycarbonyl-.beta.,.beta.-diphenylbutyronitrile:
41 g of bromobenzene dissolved in 100 ml of anhydrous ether are
added over a period of 1 hour 20 minutes, with stirring, to 6.3 g
of magnesium turnings and 240 ml of anhydrous ether. The mixture is
refluxed for 2 hours and then, over a period of 30 minutes, 51 g of
ethyl(.alpha.-methylbenzylidene)-cyanoacetate in 150 ml of ether
are added. After having been heated for 5 hours, the reaction
mixture is hydrolysed with 150 ml of 2N HCl. The organic layer is
decanted. The aqueous layer is extracted twice with 100 ml of ether
each time. The ethereal phases are combined, washed with 100 ml of
water, dried over MgSO.sub.4 and, after filtration, concentrated
under water-jet vacuum.
Distillation of the residue yields 30.7 g of the desired product
(b.p./.sub.13 Pa =150.degree.-155.degree. C.), yield: 46%.
c) .alpha.-Carboxy-.beta.,.beta.-diphenylbutyronitrile:
15 g of .alpha.-ethoxycarbonyl-.beta.,.beta.-diphenylbutyronitrile,
65 ml of ethanol, 18.4 g of potassium hydroxide pellets and 30 ml
of water are stirred at room temperature for 4 hours. After
concentration in vacuo, the residue is taken up in 150 ml of water.
After extracting 3 times with 50 ml of ether each time, the aqueous
layer is acidified with 22 ml of concentrated HCl and extracted 3
times with 100 ml of ether each time. The organic layers are
combined, dried over MgSO.sub.4 and evaporated. 14 g of the desired
product are obtained.
d) .beta.,.beta.-Diphenylbutyronitrile:
14 g of .alpha.-carboxy-.beta.,.beta.-diphenylbutyronitrile and 85
ml of triethylene glycol are heated at 80.degree. C. for 30 minutes
and then, after cooling, diluted with 300 ml of water. After
extracting 3 times with 150 ml of ether each time, drying the
organic layer and concentrating in vacuo, and purifying by
chromatography, 7.3 g of .beta.,.beta.-diphenylbutyronitrile are
obtained. Yield: 64%.
e) .beta.,.beta.-Diphenylbutyric acid:
7.2 g of the product obtained in d), 9.6 ml of concentrated
sulphuric acid, 12 ml of water and 12 ml of acetic acid are
maintained at reflux for 22 hours. After cooling and treating with
90 ml of water, the resulting precipitate is suction-filtered and
washed with water. After drying and recrystallisation from 20 ml of
cyclohexane, 6.5 g of the desired acid are obtained, m.p.
100.degree. C., yield: 77%.
f) .beta.,.beta.-Diphenylbutyryl chloride:
6.5 g of the acid above are added over a period of 15 minutes to 10
ml of thionyl chloride. After heating for 2 hours at reflux, the
solution obtained is concentrated in vacuo and the residue is taken
up twice with 50 ml of benzene with evaporation each time. 6.6 g of
.beta.,.beta.-diphenylbutyryl chloride are obtained.
g) Para-{2-[N-(3-methyl-3,3-diphenylpropionyl)amino]ethyl}benzoic
acid:
31.5 g of triethylamine are added, with stirring, to a suspension
of 5.2 g of para-[.beta.-(amino)ethyl]benzoic acid hydrochloride in
200 ml of anhydrous dimethylformamide, then 6.5 g of the chloride
obtained in f) dissolved in 75 ml of anhydrous THF are poured in
over a period of 15 minutes. The temperature rises from 26.degree.
to 34.degree. C. After stirring for 4 hours at room temperature,
then for 5 hours at 40.degree. C., the triethylamine hydrochloride
formed is suction-filtered off and the filtrate is concentrated in
vacuo. The residue is taken up in 60 ml of water. The precipitate
formed is suction-filtered, dried in air and then recrystallised
from 50 ml of anhydrous isopropanol. 5 g of
para-{2-[N-(3-methyl-3,3-diphenylpropionyl)amino]ethyl}benzoic acid
are obtained, m.p.: 211.degree. C.
EXAMPLE 10
Pharmacological Study
A. Study of the Effect of an Acute Treatment Administered by Portal
Perfusion to Conscious Rats
1. Aim of the experiment
The technique of portal perfusion in conscious rats makes it
possible to study the effect of pharmacological substances on
modifications of the tolerance to glucose administered by the
intravenous route.
The injections of agents directly into the portal circulation makes
it possible to avoid the effects of gastric transit, absorption and
release of hormone through the intestinal wall and thus to
explore:
both the direct effect on the hepatic tissue
and the existence of a liver-central nervous system-peripheral
tissue relay (liver, muscle or endocrinal target).
2. Protocol
2.1 Animals used
In this experiment, adult male SPRAGUE DAWLEY rats were used in
groups of 5 to 12 animals.
The rats used, aged 52 weeks, exhibit
a reduction in glucose tolerance,
an increase in basal insulinemia, and
an increase in plasma lipids.
The housing (from 9 to 52 weeks) of these rats was effected in a
chamber at a temperature regulated at from 21.degree. to 22.degree.
C. subjected to a fixed cycle of light (from 7.30 to 19.30 hours)
and darkness (from 19.30 to 7.30 hours). Their food consisted of a
maintenance diet (UAR A 03); water and food were supplied "ad
libitum", with the exception of the night-fasting preceding the
tests, when the food was removed.
2.2 Methods
Surgical preparation:
On d.sub.7 before the beginning of the experiment, the rats are
anaesthetized with ketamine (IMALGENE 1000-Rhone MERIEUX), and a
Silastic catheter (602-135, medical grade, DOW CORNING MIDLAND) is
implanted in the hepatic portal vein [cf. Strubbe J. H., Wolsink J.
G., Schutte A. M., Balkan B., and Prins A. J. A.: Hepatic-portal
and cardiac infusion of CKK-8 and glucagon induce different effects
on feeding. Physiology and Behavior 46, 643-646 (1989)] for the
perfusion of physiological solute (day control) and then the
product to be tested. They are then placed individually in
plexiglass cages.
After recovery, that is to say approximately 10 days later, a
second Silastic catheter (602-155, medical grade, DOW CORNING
MIDLAND) is introduced up into the right auricle through the right
jugular vein [cf. Steffens A. B.: Method for frequent sampling of
blood and continuous infusion of fluids in the rat without
disturbing the animal. Physiology and behavior 4, 833-836 (1969)].
During the test, various blood samples will be taken and the
intra-cardiac injection of a glucose bolus will be carried out
using that catheter.
During the two surgical procedures, the catheters are slid under
the skin and exited at the top of the head by means of a polished
needle bent back and plugged by a polyethylene (PE) cap closed with
the candle.
0.4 ml of a 500 U/ml heparin solution (ROUSSEL UCLAF) followed by
0.1 ml of PVP (30% polyvinylpyrrolidone solution-MW 25000-MERCK)
are introduced into the catheters before closure with the
polyethylene cap.
The viscosity of the PVP makes it possible to avoid a reflux of
blood into the catheter.
The day before each experiment, the rats are subject to 18 hours of
night fasting. On the day of the experiment these rats are weighed
and the catheters are checked to ensure they are working
properly.
In order to eliminate the stress of connecting the catheters to the
externalised needles on top of the head, 20 minutes' rest is
required before the experiment is started.
The intraportal perfusions, carried out using a No. 3 polyethylene
catheter, take 60 minutes; they have a constant flow of 2 ml/hour,
that is to say approximately 0.033 ml/minute, ensured by a BRAUN
perfuser. An IVGTT test (intravenous administration glucose
tolerance test) is carried out 30 minutes after the beginning of
the portal perfusion.
The control experiment (reference test) consists in the perfusion
of a saline solution (0.9% isotonic sodium chloride BIOSEDRA),
which permits the determination of the basal value of tolerance (K)
towards a dose of glucose for each rat.
In normal rats, insulin resistance can be induced by an intraportal
infusion of amylin (IAPP, insulinoma associated pancreatic
polypeptide) at 26 nmoles/kg/h for 90 minutes.
0.40 ml blood samples are taken (No. 6 polyethylene catheter)
immediately before the perfusion and 30 minutes after the beginning
of the perfusion. These samples are used to determine the basal
glycemia and basal insulinemia. Immediately after collecting basal
no. 2, that is to say 30 minutes after the beginning of the
perfusion, a glucose bolus is administered (1 ml/kg of a 50%
glucose solution) into the jugular vein. A series of samples are
then taken every 3 minutes from t+30 to t+60 minutes after
administration of the bolus. A 0.40 ml volume is taken each time
and replaced by 0.40 ml of physiological heparin serum.
Satisfactory functioning of the catheters is ensured by injecting
PVP between each experiment.
Collection of the samples:
To determine the glycemia, the blood is collected in URAC
(deproteinating solution) using 20 .mu.l of blood per 200 .mu.l of
URAC (1/10 dilution).
The samples destined for the determining the insulinemia are
collected over heparin (20 .mu.l of physiological heparin serum at
500 Ul/ml, that is 7.5 Ul of heparin per tube to be
centrifuged).
All the tubes are placed in ice as soon as the samples are
collected. The samples are then centrifuged for 10 minutes at 3000
revs/min (refrigerated centrifuge) to separate the substances
present as quickly as possible.
The sera (in URAC for glycemia) and the plasmae (insulinemia) are
then distributed into Eppendorf tubes which are placed in the
freezer (-20.degree. C.) until the day of the determination.
Analytical procedures:
Determination of the glycemia:
The blood glucose is measured by the glucose oxidase method using a
Boehringer kit.
A quality control is effected by determining standard values and
control values.
Measurement of glucide assimilation:
(cf. Conard v.: Mesure de l'assimilation du glucose, bases
theoriques et applications cliniques [Measurement of the
assimilation of glucose, theoretical basis and clinical
applications], "acta medica belgica" editions (1959)).
The rate of glucose desappearance following glucose loading is
expressed by the angular coefficient K of the straight line log
c=log A-Kt obtained on semi-logarithmic paper entering the time
(min) on the abscissa and the ln [glucose] on the ordinate. This
coefficient is calculated for the glycemia values corresponding to
the times between the 6th and the 30th minute after administration
of the bolus. The calculation is carried out by a computer, using a
linear regression program, after verification by graphic
representation.
This coefficient of glucide assimilation is considered as a
constant, characteristic of a given subject.
Determination of the insulinemia:
Immunoreactive plasma insulin (IRI) is determined by a PHARMACIA
Phadeseph kit radioimmunological method, a solid-phase double
antibody technique.
The determination of the standards and of the samples is carried
out in duplicate.
Preparation of the solutions:
For the control experiment (reference test):
Intraportal perfusion of 0.9% isotonic sodium chloride
(BIOSEDRA)
For the intraportal perfusion of the pharmacological reactant:
A stock solution with 1 mg of base product per ml of distilled
water is produced and used to prepare the final solution (in 0.9%
NaCl).
Results
The results are given in the following Tables Ia and Ib.
TABLE Ia
__________________________________________________________________________
Insulinemia Glucose Basal insulinemia Peak insulinemia 30 min after
tolerance SDCD male rats .mu.U/ml .mu.U/ml glucose .mu.U/ml
K10.sup.-2 52 weeks % change % change % change %
__________________________________________________________________________
Control 24.06 .+-. 3.03 57.4 .+-. 13.7 29.0 .+-. 3.7 2.72 .+-. 0.23
Benfluorex -42% p < 0.05 -5% NS -36% NS +50% p = 0.025 7.5
.mu.g/kg/min .times. 60 min Dimethyl biguanide inactive 15
.mu.g/kg/min .times. 60 min Product of Example 1 0.25 .mu.g/kg/min
.times. 60 min -42% p < 0.05 0 -21% NS +3% NS 0.50 .mu.g/kg/min
.times. 60 min -6% p < 0.01 -21% NS -69% p < 0.001 +40% p =
0.025 0.75 .mu.g/kg/min .times. 60 min -25% p = 0.05 +10% NS -36%
NS +60% p = 0.005
__________________________________________________________________________
An intraportal catheter and an intracardiac catheter (right
auricle) are implanted in 52week-old SDCD rats. After postsurgical
recovery, the various groups of rats are subjected to an 18hour
fast. The rats are conscious during the experiment. The products
are administered by intraportal perfusion for a period of 1 hour.
An induced hyperglycaemia test is effected 30 minutes after the
beginning of the perfusion which is continued during the IVGTT.
TABLE Ib
__________________________________________________________________________
Insulin resistance induced by an intraportal infusion of amylin to
12-week-old SD rats Insulin levels 24 Basal insulin Peak insulin
min after glucose Glucose tolerance levels (.mu.U/ml) levels
(.mu.U/ml) (.mu.U/ml) K .multidot. 10.sup.-2
__________________________________________________________________________
Control 5.93 .+-. 0.48 24.80 .+-. 1.86 8.86 .+-. 0.77 3.54 .+-.
0.24 Amylin 6.87 .+-. 0.77 23.54 .+-. 1.7 15.28 .+-. 1.90 1.71 .+-.
0.27 Amylin + product 8.26 .+-. 1.15 23.60 .+-. 2.17 15 .+-. 1.86
3.79 .+-. 0.38 of Example 1 (0.75 .mu.g/kg/min for 60 mn)
__________________________________________________________________________
B. STUDY OF THE EFFECT OF A CHRONIC TREATMENT ADMINISTERED PER OS
TO 52-WEEK-OLD MALE SDCD RATS
1. Aim of the experiment
The tests are carried out on rats that have weight anomalies
associated with hyperinsulism and hyperglyceridemia.
The following are investigated:
on the one hand the effect of a prolonged treatment with the
product of Example 1 and the reference substances on those
anomalies, and
on the other hand the consumption of glucose by the adipose tissue
is measured in the basal state and in the presence of insulin
(10.sup.-9 M).
2. Protocol
2.1 Animals used
Rats identical to those in the acute treatment study are used (cf.
paragraph A-2.1 hereinabove), that is male SDCD rats aged 52
weeks.
2.2 Methods
9 days before the beginning of the experiment (d.sub.-9), the rats
are divided into groups by stratified randomisation based on
weight.
5 days before the beginning of the experiment (d.sub.-5) the rats
are conditioned by administering a gum solution.
The first day of the experiment (d.sub.1), the products to be
tested are administered to the rats at different doses twice per
day. More precisely, the products are administered suspended in the
gum between 9.00 and 10.00 hours and 16.00 and 17.00 hours for 14
days. The treated animals are weighed daily.
On day 15 the rats (fasted for 18 hours) are sacrificed by
decapitation. The blood is immediately collected in a cupule. An
amount (50 .mu.l) is transferred into 500 .mu.l of uranyl acetate
for determining the glycemia. An amount of 3 ml is transferred into
a tube containing a solution of heparin (30 .mu.l per 1 ml of whole
blood) and centrifuged to separate the plasma. Another amount of
300 .mu.l is transferred to a tube containing 15 .mu.l of a
solution of EDTA/NaF for determining the lactates.
Epididymal adipose tissue is taken for metabolic study immediately
after sacrifice.
For each animal, two fragments of right and left epididymal tissue
are minced with scissors and distributed in 6 incubation flasks.
Three of those flasks contain 500 .mu.l of medium and the others
500 .mu.l of medium to which porcine insulin (10.sup.-9 M) has been
added; the production of CO.sub.2 is thus measured in triplicate
for each of the rats from each group.
2.3 Results
The results are given in the following Table II
TABLE II
__________________________________________________________________________
Treatment of Basal insulin- Glycermia Glucose toler- Triglyceride
Cholesterol 52-week-old % weight aemia .mu.U/ml g/l ance K
10.sup.-2 g/l g/l Cerebral male SDCD rats change % change % change
% change % change % change serotonin
__________________________________________________________________________
Control +0.4% 32 .+-. 2.4 1.06 .+-. 0.05 3.01 .+-. 0.24 3.64 .+-.
0.57 1.1 .+-. 0.14 Benfluorex 1 mg/kg .times. 2 -2% (NS) -10% NS
-10% NS +30% -43% -20% NS Reduced p < 0.05 p = 0.025 2.5 mg/kg
.times. 2 -6% p = 0.85 -16% NS -12% NS +25% -44% -30% NS Reduced p
= 0.05 p = 0.05 Product of Example 1 0.5 mg/kg .times. 2 -1.4% -12%
p = 0.5 -5% NS +26% (NS) -18% (NS) 0 unchanged P = 0.005 p = 0.088
1.0 mg/kg .times. 2 -1.9% -20% p = 0.2 +10% NS +41% -38% -8% (NS)
unchanged p = 0.005 p = 0.064 2.5 mg/kg .times. 2 -3.6% -41% -10%
NS +59% -50% -34% unchanged p = 0.005 p = 0.005 p = 0.025 p = 0.01
p = 0.025
__________________________________________________________________________
N
C IN VITRO STUDY OF LDL OXIDATION
A comparative study between the product of Example 1 and the
reference substances (benfluorex, dimethyl biguanide) with respect
to in vitro LDL oxidation was carried out.
The results are given in the following Table III.
TABLE III
__________________________________________________________________________
Incorporation of In vitro LDL oxidation oleate in the by copper by
monocytes esters of cholesterol
__________________________________________________________________________
Benfluorex Inactive at Inactive at -30% at 10.sup.-5 M 10.sup.-4 M
10.sup.-4 M Dimethylbiguamide Inactive at Inactive at Inactive at
10.sup.-5 10.sup.-4 M 10.sup.-4 M 10.sup.-4 M M Product of
IC.sub.50 = 10.sup.-5 M IC.sub.50 = 10.sup.-5 M -70% at 10.sup.-5 M
Example 1
__________________________________________________________________________
D EXAMINATION INTO A HYPOTENSIVE EFFECT IN CONSCIOUS DOGS
The arterial pressure was measured by external pressure band
(sphygmomanometer) on the tail of the dog, before and after
treatment with the product of Example 1 at a dose of 5 mg/kg
p.o.
The results are given in the following Table IV.
TABLE IV ______________________________________ Decrease in
arterial pressure Product Animal (AP) tested (number:n) systolic AP
diastolic AP ______________________________________ Product of dog
-2.4 .times. 10.sup.3 Pa -3 .times. 10.sup.3 Pa Example 1 (n = 4)
to to (5 mg/kg -3.6 .times. 10.sup.3 Pa -5 .times. 10.sup.3 Pa
p.o.) ______________________________________
E. CONCLUSION
The results of the studies described above show the pharmacological
and therapeutic value of the levorotatory isomer of
2-[(.beta.-methoxy-.beta.-meta-trifluoromethylphenyl)ethylamino]ethyl
para-[2-(.alpha.-fluoren-9-ylacetylamino)ethyl]benzoate
hydrochloride (a particularly representative example of the
compounds of the present invention) and the originality and
superiority thereof compared with reference substances known to be
specifically adapted to the treatments in question.
* * * * *